N-(aminoheteroaryl)-1H-indole-2-carboxamide derivatives, preparation thereof and therapeutic use thereof

ABSTRACT

The invention relates to compounds of general formula (I): 
     
       
         
         
             
             
         
       
     
     Wherein n, X 1 , X 2 , X 3 , X 4 , Y, Z 1 , Z 2 , Z 3 , Z 4 , Ra and Rb are as defined herein. The invention also relates to process for the preparation of compounds of formula (I) and their therapeutic use.

This application is a continuation of International application No.PCT/FR2007/001,250, filed Jul. 20, 2007, which is incorporated herein byreference in its entirety; which claims the benefit of priority ofFrench Patent Application No. 06/06,742, filed Jul. 24, 2006.

A subject matter of the invention isN-(aminoheteroaryl)-1H-indole-2-carboxamide derivatives which exhibit anin vitro and in vivo antagonist activity for receptors of TRPV1 (or VR1)type.

A first subject matter of the invention is the compounds correspondingto the general formula (I) below.

Another subject matter of the invention is processes for the preparationof the compounds of general formula (I).

Another subject matter of the invention is the use of the compounds ofgeneral formula (I) in particular in medicaments or in pharmaceuticalcompositions.

The compounds of the invention correspond to the general formula (I):

in which:

-   X₁ represents a hydrogen or halogen atom or a C₁-C₆-alkyl,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    C₁-C₆-fluoroalkyl, cyano, C(O)NR₁R₂, nitro, C₁-C₆-thioalkyl,    —S(O)-C₁-C₆-alkyl, —S(O)₂-C₁-C₆-alkyl, SO₂NR₁R₂,    aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and    heteroaryl optionally being substituted by one or more substituents    chosen from a halogen or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,    C₁-C₆-fluoroalkoxyl, nitro or cyano group;-   X₂ represents a hydrogen or halogen atom or a C₁-C₆-alkyl,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,    C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, cyano,    C(O)NR₁R₂, C₁-C₆-thioalkyl, —S(O)-C₁-C₆-alkyl, —S(O)₂-C₁-C₆-alkyl,    SO₂NR₁R₂, aryl-C₁-C₆-alkylene, aryl or heteroaryl, the aryl and    heteroaryl optionally being substituted by one or more substituents    chosen from a halogen or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,    C₁-C₆-fluoroalkoxyl, nitro or cyano group;-   X₃ and X₄ represent, independently of one another, a hydrogen or    halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,    C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, cyano,    C(O)NR₁R₂, nitro, NR₁R₂, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,    —S(O)₂-C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅,    aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and    heteroaryl optionally being substituted by one or more substituents    chosen from a halogen or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,    C₁-C₆-fluoroalkoxyl, nitro or cyano group;-   Z₁, Z₂, Z₃ and Z₄ represent, independently of one another, a    nitrogen atom or a C(R₆) group, at least one corresponding to a    nitrogen atom and at least one corresponding to a C(R₆) group; the    nitrogen atom or one of the nitrogen atoms present in the ring,    defined as nitrogen of position 1, optionally being substituted by    R₇ when the carbon atom in the 2 or 4 position with respect to this    reference nitrogen is substituted by an oxo or thio group;-   n is equal to 0, 1, 2 or 3;-   Y represents an aryl or a heteroaryl optionally substituted by one    or more groups chosen from a halogen atom or a C₁-C₆-alkyl,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    C₁-C₆-fluoroalkyl, hydroxyl, C₁-C₆-alkoxyl,    C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, cyano,    C(O)NR₁R₂, nitro, NR₁R₂, C₁-C₆-thioalkyl, thiol, —S(O)—C₁-C₆-alkyl,    —S(O)₂-C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅, aryl-C₁-C₆-alkylene    or aryl group, the aryl and the aryl-C₁-C₆-alkylene optionally being    substituted by one or more substituents chosen from a halogen or a    C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or    cyano group;-   Ra and Rb represent, independently of one another, a hydrogen atom    or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    C₁-C₆-fluoroalkyl, hydroxyl, C₁-C₆-alkoxyl,    C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, aryl or    heteroaryl group, it being possible for Ra and Rb optionally to be    substituted by one or more Rc groups which are identical to or    different from one another;-   Rc represents a halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,    C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl,    C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, cyano,    C(O)NR₁R₂, NR₁R₂, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅, OC(O)NR₁R₂, NR₃COOR₄,    NR₃CONR₁R₂, hydroxyl, thiol, oxo, thio, aryl-C₁-C₆-alkylene, aryl or    heteroaryl group, the aryl and the heteroaryl optionally being    substituted by one or more substituents chosen from a halogen or a    C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or    cyano group;-   R₁ and R₂ represent, independently of one another, a hydrogen atom    or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    aryl-C₁-C₆-alkylene or aryl group; or R₁ and R₂ together form, with    the nitrogen atom which carries them, an azetidinyl, pyrrolidinyl,    piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl or    homopiperazinyl group, this group optionally being substituted by a    C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    aryl-C₁-C₆-alkylene, aryl or heteroaryl group;-   R₃ and R₄ represent, independently of one another, a hydrogen atom    or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    aryl-C₁-C₆-alkylene, aryl or heteroaryl group;-   R₅ represents a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene, aryl or    heteroaryl group;-   R₆ represents a hydrogen or halogen atom or a C₁-C₆-alkyl,    C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,    C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl,    C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, aryl,    aryl-C₁-C₆-alkylene, heteroaryl, hydroxyl, thiol, oxo or thio group;-   R₇ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,    C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,    C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, aryl,    aryl-C₁-C₆-alkylene or heteroaryl group.

In the compounds of general formula (I), the nitrogen atom or atoms canbe in the oxidized (N-oxide) form.

Among the compounds of general formula (I) which are subject matters ofthe invention, a first subgroup of compounds is composed of thecompounds for which X₁, X₂, X₃ and X₄ are chosen, independently of oneanother, from a hydrogen or halogen atom or a C₁-C₆-alkyl orC₁-C₆-fluoroalkyl group.

Among the compounds of general formula (I) which are subject matters ofthe invention, a second subgroup of compounds is composed of thecompounds for which X₁, X₂, X₃ and X₄ are chosen, independently of oneanother, from a hydrogen or fluorine atom or a trifluoromethyl group.

Among the compounds of general formula (I) which are subject matters ofthe invention, a third subgroup of compounds is composed of thecompounds for which X₁ and X₄ represent a hydrogen atom and X₂ and X₃are chosen, independently of one another, from a hydrogen or halogenatom or a C₁-C₆-fluoroalkyl group.

Among the compounds of general formula (I) which are subject matters ofthe invention, a fourth subgroup of compounds is composed of thecompounds for which X₁ and X₄ represent a hydrogen atom and X₂ and X₃are chosen, independently of one another, from a hydrogen or fluorineatom or a trifluoromethyl group.

Among the compounds of general formula (I) which are subject matters ofthe invention, a fifth subgroup of compounds is composed of thecompounds for which Z₁, Z₂, Z₃ and Z₄ represent, independently of oneanother, a nitrogen atom or a C(R₆) group, at least two of themcorresponding to a C(R₆) group; the nitrogen atom or one of the nitrogenatoms present in the ring, defined as nitrogen of position 1, optionallybeing substituted by R₇ when the carbon atom in the 2 or 4 position withrespect to this reference nitrogen is substituted by an oxo or thiogroup; R₆ and R₇ being as defined in the general formula (I).

Among the compounds of general formula (I) which are subject matters ofthe invention, a sixth subgroup of compounds is composed of thecompounds for which Z₁ and Z₂ represent a C(R₆) group and Z₃ and Z₄represent a nitrogen atom, R₆ being as defined in the general formula(I).

Among the compounds of general formula (I) which are subject matters ofthe invention, a seventh subgroup of compounds is composed of thecompounds for which Z₁ and Z₂ represent a C(R₆) group and Z₃ and Z₄represent a nitrogen atom, R₆ corresponding to a hydrogen atom.

Among the compounds of general formula (I) which are subject matters ofthe invention, an eighth subgroup of compounds is composed of thecompounds for which Z₁, Z₂, Z₃ and Z₄ represent, independently of oneanother, a nitrogen atom or a C(R₆) group, one corresponding to anitrogen atom and the others corresponding to a C(R₆) group; thenitrogen atom present in the ring, defined as nitrogen of position 1,optionally being substituted by R₇ when the carbon atom in the 2 or 4position with respect to this reference nitrogen is substituted by anoxo or thio group; R₆ and R₇ being as defined in the general formula(I).

Among the compounds of general formula (I) which are subject matters ofthe invention, a ninth subgroup of compounds is composed of thecompounds for which Z₁ and Z₂ represent a C(R₆) group and Z₃ and Z₄represent, independently of one another, a nitrogen atom or a C(R₆)group, one of Z₃ and Z₄ corresponding to a C(R₆) group; R₆ representinga hydrogen or halogen atom or a C₁-C₆-alkyl or C₁-C₆-fluoroalkyl group.

Among the compounds of general formula (I) which are subject matters ofthe invention, a tenth subgroup of compounds is composed of thecompounds for which Z₁ and Z₂ represent a C(R₆) group and Z₃ and Z₄represent, independently of one another, a nitrogen atom or a C(R₆)group, one of Z₃ and Z₄ corresponding to a C(R₆) group; R₆ representinga hydrogen or fluorine atom or a methyl or trifluoromethyl group.

Among the compounds of general formula (I) which are subject matters ofthe invention, an eleventh subgroup of compounds is composed of thecompounds for which Z₄ represents a nitrogen atom and Z₁, Z₂ and Z₃represent, independently of one another, a C(R₆) group; the nitrogenatom present in the ring, defined as nitrogen of position 1, optionallybeing substituted by R₇ when the carbon atom in the 2 or 4 position withrespect to this reference nitrogen is substituted by an oxo or thiogroup; R₆ and R₇ being as defined in the general formula (I).

Among the compounds of general formula (I) which are subject matters ofthe invention, a twelfth subgroup of compounds is composed of thecompounds for which Z₄ represents a nitrogen atom and Z₁, Z₂ and Z₃represent, independently of one another, a C(R₆) group, R₆ representinga hydrogen or halogen atom or a C₁-C₆-alkyl or C₁-C₆-fluoroalkyl group.

Among the compounds of general formula (I) which are subject matters ofthe invention, a thirteenth subgroup of compounds is composed of thecompounds for which Z₄ represents a nitrogen atom and Z₁, Z₂ and Z₃represent, independently of one another, a C(R₆) group, R₆ representinga hydrogen or fluorine atom or a methyl or trifluoromethyl group.

Among the compounds of general formula (I) which are subject matters ofthe invention, a fourteenth subgroup of compounds is composed of thecompounds for which n is equal to 1.

Among the compounds of general formula (I) which are subject matters ofthe invention, a fifteenth subgroup of compounds is composed of thecompounds for which Y represents an aryl or heteroaryl optionallysubstituted by one or more halogen atoms.

Among the compounds of general formula (I) which are subject matters ofthe invention, a sixteenth subgroup of compounds is composed of thecompounds for which Y represents a phenyl or a pyridinyl, the phenyloptionally being substituted by a halogen atom.

Among the compounds of general formula (I) which are subject matters ofthe invention, a seventeenth subgroup of compounds is composed of thecompounds for which Ra and Rb represent, independently of one another, ahydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, hydroxyl,C₁-C₆-alkoxyl or C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O— group, it beingpossible for Ra and Rb to be optionally substituted by one or more Rcgroups which are identical to or different from one another;

-   Rc represents a C₁-C₆-alkoxyl, NH₂ or hydroxyl group.

Among the compounds of general formula (I) which are subject matters ofthe invention, an eighteenth subgroup of compounds is composed of thecompounds for which Ra and Rb represent, independently of one another, ahydrogen atom or a C₁-C₆-alkyl or C₃-C₇-cycloalkyl group, it beingpossible for Ra and Rb to be optionally substituted by one or more Rcgroups which are identical to or different from one another; Rcrepresents an oxo group.

Among the compounds of general formula (I) which are subject matters ofthe invention, a nineteenth subgroup of compounds is composed of thecompounds for which Ra and Rb represent, independently of one another, ahydrogen atom or a methyl, propyl or cyclopropyl group, it beingpossible for Ra and Rb to be optionally substituted by an Rc group whereRc represents an oxo group.

Among the compounds of general formula (I) which are subject matters ofthe invention, a twentieth subgroup of compounds is composed of thecompounds for which X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄, n, Y, Ra and Rb areas defined in the general formula (I), provided that, when Y representsan unsubstituted phenyl, then n is equal to 2 or 3.

Among the compounds of general formula (I) which are subject matters ofthe invention, a twenty-first subgroup of compounds is composed of thecompounds for which X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄, n, Y, Ra and Rb areas defined in the above subgroups.

Among the compounds of general formula (I) which are subject matters ofthe invention, a twenty-second subgroup of compounds is composed of thecompounds for which

-   X₁, X₂, X₃ and X₄ are chosen, independently of one another, from a    hydrogen or halogen atom or a C₁-C₆-alkyl or C₁-C₆-fluoroalkyl    group; and/or-   Z₁, Z₂, Z₃ and Z₄ represent, independently of one another, a    nitrogen atom or a C(R₆) group, one corresponding to a nitrogen atom    and the others corresponding to a C(R₆) group; the nitrogen atom    present in the ring, defined as nitrogen of position 1, optionally    being substituted by R₇ when the carbon atom in the 2 or 4 position    with respect to this reference nitrogen is substituted by an oxo or    thio group; R₆ and R₇ being as defined in the general formula (I);    and/or-   n is equal to 1; and/or-   Ra and Rb represent, independently of one another, a hydrogen atom    or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,    C₁-C₆-fluoroalkyl, hydroxyl, C₁-C₆-alkoxyl or    C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O— group, it being possible for Ra    and Rb to be optionally substituted by one or more Rc groups which    are identical to or different from one another;-   Rc represents a C₁-C₆-alkoxyl, NH₂ or hydroxyl group.

Mention may be made, among the compounds of general formula (I) whichare subject matters of the invention, of the following compounds:

-   1.    N-[6-(methylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   2.    N-[6-(dimethylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide    hydrochloride (1:1)-   3.    N-[6-(methylamino)pyridin-3-yl]-5-fluoro-1-benzyl-1H-indole-2-carboxamide-   4.    N-[6-(dimethylamino)pyridin-3-yl]-5-fluoro-1-benzyl-1H-indole-2-carboxamide-   5.    N-[6-(dimethylamino)pyridin-3-yl]-6-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   6.    N-[5-(dimethylamino)pyridin-2-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   7.    N-[6-(methylamino)pyridin-3-yl]-5-fluoro-1-(2-fluorobenzyl)-1H-indole-2-carboxamide-   8.    N-[6-(1-propylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide    hydrochloride (1:1)-   9.    N-[6-(cyclopropylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide    hydrochloride (1:1)-   10.    N-[6-(dimethylamino)pyridin-3-yl]-5-fluoro-1-(4-fluorobenzyl)-1H-indole-2-carboxamide    and its hydrochloride salt (1:1)-   11.    N-[6-(acetylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   12.    N-[6-(dimethylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   13.    N-[6-dimethylamino-4-methylpyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   14.    N-[6-(acetylamino)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   15.    N-[6-methylamino-4-methylpyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   16.    N-[6-dimethylamino-5-methylpyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   17.    N-[6-dimethylamino-4-methylpyridin-3-yl]-5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxamide-   18.    N-[6-methylamino-4-methylpyridin-3-yl]-5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxamide-   19.    N-[6-dimethylamino-5-methylpyridin-3-yl]-5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxamide-   20.    N-[6-dimethylamino-5-(trifluoromethyl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   21.    N-[6-methylamino-2-methylpyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   22.    N-[5-(dimethylamino)pyridazin-2-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide    and its hydrochloride salt (1:1)-   23.    N-[5-(dimethylamino)pyridazin-2-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   24.    N-[5-(dimethylamino)pyridazin-2-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   25.    N-[5-(dimethylamino)pyridazin-2-yl]-5-trifluoromethyl-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxamide    hydrochloride (1:1)-   26.    N-[6-(methylamino)pyridin-3-yl]-5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxamide-   27.    N-[6-dimethylamino-5-fluoropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide-   28.    N-[6-dimethylamino-4-(trifluoromethyl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

In the context of the present invention:

-   -   C_(t)-C_(z) where t and z can take the values from 1 to 7 is        understood to mean a carbon chain which can have from t to z        carbon atoms, for example C₁-C₃ is understood to mean a carbon        chain which can have from 1 to 3 carbon atoms;    -   an alkyl is understood to mean a saturated, linear or branched,        aliphatic group. Mention may be made, by way of examples, of the        methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or        pentyl groups, and the like;    -   an alkylene is understood to mean a saturated, linear or        branched, divalent alkyl group; for example, a C₁₃-alkylene        group represents a linear or branched divalent carbon chain of 1        to 3 carbon atoms, for example a methylene, ethylene,        1-methylethylene or propylene;    -   a cycloalkyl is understood to mean a cyclic carbon group.        Mention may be made, by way of examples, of the cyclopropyl,        cyclobutyl, cyclopentyl or cyclohexyl groups, and the like;    -   a fluoroalkyl is understood to mean an alkyl group, one or more        hydrogen atoms of which have been substituted by a fluorine        atom;    -   an alkoxy is understood to mean an —O-alkyl radical where the        alkyl group is as defined above;    -   a fluoroalkoxy is understood to mean an alkoxy group, one or        more hydrogen atoms of which have been substituted by a fluorine        atom;    -   a thioalkyl is understood to mean an —S-alkyl radical where the        alkyl group is as defined above;    -   an aryl is understood to mean an aromatic cyclic group        comprising between 6 and 10 carbon atoms.

Mention may be made, as examples of aryl groups, of the phenyl ornaphthyl groups;

-   -   a heteroaryl is understood to mean a 5- to 10-membered aromatic        cyclic group comprising from 1 to 4 heteroatoms chosen from O, S        or N. Mention may be made, by way of examples, of the        imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl,        oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,        pyridazinyl, indolyl, benzofuranyl, benzothiophenyl,        benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl,        isobenzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl or        quinoxalinyl groups;    -   a halogen atom is understood to mean a fluorine, a chlorine, a        bromine or an iodine;    -   “oxo” means “═O”;    -   “thio” means “═S”.

The compounds of formula (I) can comprise one or more asymmetric carbonatoms. They can thus exist in the form of enantiomers or ofdiastereoisomers. These enantiomers or diastereoisomers, and theirmixtures, including racemic mixtures, come within the invention.

The compounds of formula (I) can exist in the form of bases or ofaddition salts with acids. Such addition salts come within theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids but the salts of other acids, for example of use in thepurification or the isolation of the compounds of formula (I), also comewithin the invention.

The compounds of general formula (I) can occur in the form of hydratesor of solvates, namely in the form of combinations or associations withone or more molecules of water or with a solvent. Such hydrates andsolvates also come within the invention.

In what follows, the term “leaving group” is understood to mean a groupwhich can be easily split from a molecule by cleavage of a heterolyticbond with departure of an electron pair. This group can thus be easilyreplaced by another group, for example during a substitution reaction.Such leaving groups are, for example, halogens or an activated hydroxylgroup, such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate,triflate, acetate, and the like. Examples of leaving groups andreferences for their preparation are given in “Advances in OrganicChemistry”, J. March, 5^(th) edition, Wiley Interscience, 2001.

In accordance with the invention, the compounds of general formula (I)can be prepared according to the process illustrated by the followingscheme 1.

According to scheme 1, the compounds of general formula (IV) can beobtained by reaction of a compound of general formula (II), in which X₁,X₂, X₃ and X₄ are as defined in the general formula (I) and B representsa C₁-C₆-alkoxyl group, with a compound of general formula (III), inwhich Y and n are as defined in the general formula (I) and LGrepresents a leaving group where LG represents a hydroxyl group.

The compounds of general formula (II) are available commercially or areprepared according to numerous processes described in the literature (D.Knittel, Synthesis, 1985, 2, 186; T. M. Williams, J. Med. Chem., 1993,36(9), 1291; JP2001151771A2, for example).

When the compound of general formula (III) is defined such that n isequal to 1, 2 or 3 and LG represents a leaving group such as a chlorine,bromine or iodine atom, the reaction can be carried out in the presenceof a base, such as sodium hydride or potassium carbonate, in a polarsolvent, such as dimethylformamide, dimethyl sulfoxide or acetone (n=1:Kolasa T., Bioorg. Med. Chem., 1997, 5(3), 507, n=2: Abramovitch R.,Synth. Commun., 1995, 25(1), 1). When the compound of general formula(III) is defined such that n is equal to 1, 2 or 3 and LG represents ahydroxyl group, the compounds of general formula (IV) can be obtained byreaction of the compound of general formula (II) with a compound ofgeneral formula (III) in the presence of a phosphine, such as, forexample, triphenylphosphine, and of a reactant, such as, for example,diethyl azodicarboxylate, in solution in a solvent, such asdichloromethane or tetrahydrofuran (O. Mitsonobu, Synthesis, 1981,1-28).

When the compound of general formula (III) is defined such that n isequal to 0 and LG represents a leaving group such as a chlorine, bromineor iodine atom, the reaction can be carried out at a temperature ofbetween 80° C. and 250° C. in the presence of a copper-based catalyst,such as copper bromide or copper oxide, and of a base, such as potassiumcarbonate (Murakami Y., Chem. Pharm. Bull., 1995, 43(8), 1281). It isalso possible to use the milder conditions described in S. L. Buchwald,J. Am. Chem. Soc., 2002, 124, 11684.

The compound of general formula (IV) for which B represents aC₁-C₆-alkoxyl group can be converted to the compound of general formula(IV) where B represents a hydroxyl group by the action of a base, suchas sodium hydroxide or potassium hydroxide, in solution in a solvent,such as ethanol. The compound of general formula (IV) where B representsa hydroxyl group can subsequently be converted to the compound ofgeneral formula (IV) where B represents a chlorine atom by the action ofa chlorinating agent, such as thionyl chloride, in a solvent, such asdichloromethane.

The compound of general formula (I) can subsequently be obtained, forexample, by reaction of a compound of general formula (IV) where B is achlorine atom, as obtained above, with an amine of general formula (V),in which Z₁, Z₂, Z₃, Z₄, Ra and Rb are as defined in the general formula(I), in a solvent, such as dichloroethane, toluene or tetrahydrofuran.

The compound of general formula (I) can also be obtained by reaction ofa compound of general formula (IV) where B is a hydroxyl group, asobtained above, with an amine of general formula (V), in which Z₁, Z₂,Z₃, Z₄, Ra and Rb are as defined in the general formula (I) in thepresence of a coupling agent, such as diethyl cyanophosphonate, in thepresence of a base, such as triethylamine, in a solvent, such asdimethylformamide.

The compounds of general formulae (I), (II) and (IV) in which X₁, X₂, X₃and/or X₄ represent a cyano group or an aryl can be obtained by acoupling reaction, catalyzed by a metal, such as palladium, carried outon the corresponding compounds of general formulae (I), (II) and (IV) inwhich X₁, X₂, X₃ and/or X₄ represent a leaving group, for example abromine, according to methods which are described in the literature orwhich are known to a person skilled in the art.

The compounds of general formulae (I), (II) and (IV) in which X₁, X₂, X₃and/or X₄ represent a C(O)NR₁R₂ group can be obtained from thecorresponding compounds of general formulae (I), (II) and (IV) in whichX₁, X₂, X₃ and/or X₄ represent a cyano group according to methods whichare described in the literature or which are known to a person skilledin the art.

The compounds of general formulae (I), (II) and (IV) in which X₁, X₂,X₃, X₄ and/or R₆ correspond to an —S(O)-alkyl or —S(O)₂-alkyl group canbe obtained by oxidation of the corresponding compounds of generalformulae (I), (II) and (IV) in which X₁, X₂, X₃, X₄ and/or R₆ representa C₁-C₆-thioalkyl group according to methods which are described in theliterature or which are known to a person skilled in the art.

Likewise, the compounds of general formulae (I) and (IV) in which Y issubstituted by an —S(O)-alkyl or —S(O)₂-alkyl group can be obtained byoxidation of the corresponding compounds of general formulae (I) and(IV) in which Y is substituted by a C₁-C₆-thioalkyl group according tomethods which are described in the literature or which are known to aperson skilled in the art.

The compounds of general formula (I) in which Z₁, Z₂, Z₃ and/or Z₄represent a C(R₆) group where R₆ represents a hydroxyl group can beobtained from the corresponding compounds of general formula (I) inwhich Z₁, Z₂, Z₃ and/or Z₄ represent a C(R₆) group where R₆ represents aC₁-C₆-alkoxyl group according to methods which are described in theliterature or which are known to a person skilled in the art.

The compounds of general formulae (I), (II) and (IV) in which X₁, X₂, X₃and/or X₄ represent an NR₁R₂, NR₃COR₄ or NR₃SO₂R₅ group can be obtainedfrom the corresponding compounds of general formulae (I), (II) and (IV)in which X₁, X₂, X₃ and/or X₄ represent a nitro group, for example byreduction and then acylation or sulfonylation, according to methodswhich are described in the literature or which are known to a personskilled in the art.

The compounds of general formulae (I), (II) and (IV) in which X₁, X₂, X₃and/or X₄ represent an NR₁R₂, NR₃COR₄ or NR₃SO₂R₅ group can be obtainedfrom the corresponding compounds of general formulae (I), (II) and (IV)in which X₁, X₂, X₃ and/or X₄ represent, for example, a bromine atom bya coupling reaction respectively with an amine, an amide or asulfonamide in the presence of a base, of a phosphine and of apalladium-based catalyst according to methods which are described in theliterature or which are known to a person skilled in the art.

The compounds of general formulae (I), (II) and (IV) in which X₁, X₂, X₃and/or X₄ represent an SO₂NR₁R₂ group can be obtained by a methodanalogous to that described in Pharmazie, 1990, 45, 346, or according tomethods which are described in the literature or which are known to aperson skilled in the art.

The compounds of general formula (I) in which NRaRb corresponds to anNH₂ group can be obtained, according to conditions known to a personskilled in the art and described in the literature (Greene and Wuts,Protective Groups in Organic Synthesis, Wiley-Interscience), fromprecursors of general formula (I) where NRaRb =NH-PG, PG correspondingto a protective group, such as an acetyl or tert-butoxycarbonyl group.

The compounds of general formula (III) are commercially available, aredescribed in the literature (Carling R. W. et al., J. Med. Chem., 2004(47), 1807-1822, or Russel M. G. N. et al., J. Med. Chem., 2005 (48),1367-1383) or are accessible using methods known to a person skilled inthe art. Some compounds of general formula (IV) are described in theliterature (for example WO2007/010144). The compounds (V) and the otherreactants, when their method of preparation is not described, arecommercially available or are described in the literature (for exampleWO05028452, WO02048152, WO06040522, WO04052869, WO04/062665,JP540028330, GB 870 027, U.S. Pat. No. 4,104,385, WO04110985,Heterocycles, 1977, 6(12), 1999-2004).

The invention, according to another of its aspects, also has as subjectmatter the compounds of general formulae (Va) and (Vb). These compoundsare of use as intermediates in the synthesis of the compounds of formula(I).

The amines Va and Vb are prepared according to the processes describedin examples Nos. 8 and 10.

The following examples describe the preparation of some compounds inaccordance with the invention. These examples are not limiting and serveonly to illustrate the present invention. The numbers of the compoundsexemplified refer to those given in table 1. The elementalmicroanalyses, the LC-MS (liquid chromatography coupled to massspectrometry) analyses, the IR spectra and the NMR spectra confirm thestructures of the compounds obtained.

EXAMPLE 1 Compound No. 1N-[6-(Methylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

1.1 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid

An aqueous sodium hydroxide solution, prepared from 1.15 g (28.92 mmol)of sodium hydroxide pellets in 50 ml of water, is added to a solution of7.6 g (24.10 mmol) of ethyl5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (WO2006/024776) in241 ml of ethanol. The mixture is heated for two hours and thenconcentrated under reduced pressure. The resulting solid is taken up in200 ml of water. The solution is washed with two times 100 ml of ethylether, acidified by successive additions of small amounts ofconcentrated hydrochloric acid and then extracted with 200 ml of ethylacetate. The organic phase is finally washed twice with 100 ml of waterand once with 50 ml of a saturated sodium chloride solution, dried overmagnesium sulfate and concentrated under reduced pressure. After dryingat 50° C. under reduced pressure, 6.4 g of the expected product areobtained in the form of a solid which will be used as is in thefollowing stage.

1.2N-[6-(Methylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide(Compound No. 1)

0.27 ml (1.67 mmol) of diethyl cyanophosphonate is added dropwise at 20°C. under argon to a solution of 0.4 g (1.39 mmol) of5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (obtained instep 1.1) and 0.216 g (1.67 mmol) of 3-amino-6-(methylamino)pyridine(WO2005/028452) in 10 ml of dry dimethylformamide. The mixture isstirred for 10 minutes and then 0.43 ml (3.08 mmol) of triethylamine isadded dropwise. The mixture is stirred at ambient temperature for 18hours and concentrated under reduced pressure, and then the residue istaken up in 50 ml of ethyl acetate. This solution is then successivelywashed with three times 20 ml of a saturated sodium hydrogencarbonatesolution, 50 ml of water and 20 ml of a saturated sodium chloridesolution and then dried over sodium sulfate, filtered and concentratedunder reduced pressure. The solid obtained is triturated from hotisopropyl ether. 0.471 g of a solid is obtained, which solid is driedunder reduced pressure.

Melting point: 225-227° C.

¹H NMR (d₆-DMSO), δ (ppm): 2.61 (d, 3H); 5.82 (s, 2H); 6.3 (q, 1H); 6.41(d, 1H); 7.02 (m, 6H); 7.49 (m, 2H); 7.65 (d×d, 1H); 8.2 (d, 1H); 10.15(s, 1H)

EXAMPLE 2 Compound No. 2N-[6-(Dimethylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamidehydrochloride (1:1) 2.1N-[6-(Dimethylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

0.27 ml (1.67 mmol) of diethyl cyanophosphonate is added dropwise at 20°C. under argon to a solution of 0.4 g (1.39 mmol) of5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (obtained inExample 1.1) and 0.229 g (1.67 mmol) of3-amino-6-(dimethylamino)pyridine in 3.5 ml of dry dimethylformamide.The mixture is stirred for 10 minutes and then 0.43 ml (3.06 mmol) oftriethylamine is added dropwise. The mixture is stirred at ambienttemperature for 18 hours and concentrated under reduced pressure, andthen the residue is taken up in 50 ml of ethyl acetate. This solution isthen successively washed with three times 20 ml of a saturated sodiumhydrogencarbonate solution, 50 ml of water and 20 ml of a saturatedsodium chloride solution and then dried over sodium sulfate, filteredand concentrated under reduced pressure. The solid obtained istriturated from hot isopropyl ether. 0.423 g of a solid is collected byfiltration, which solid is dried under reduced pressure and used as inthe following stage.

2.2N-[6-(Dimethylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamidehydrochloride (1:1) (Compound No. 2)

A suspension of the solid obtained in stage 2.1 in isopropyl ether and a4N solution of hydrochloric acid in dioxane is stirred at 0° C. Thesolid is collected by filtration, dried, again triturated from hotisopropyl ether, collected by filtration and dried under reducedpressure.

Melting point: 232-234° C.; HCl (1:1)

¹H NMR (d₆-DMSO), δ (ppm): 3.2 (s, 6H); 5.85 (s, 2H) 6.80 (m, 2H); 7.0(m, 1H); 7.2 (m, 3H); 7.5 (m, 3H); 8.2 (d, 1H); 8.5 (s, 1H); 10.85 (s,1H).

EXAMPLE 3 Compound No. 12N-[6-(Dimethylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

0.185 g (1.35 mmol) of 3-amino-6-(dimethylamino)pyridine (WO2005/028452)in 2 ml of dry dimethylformamide is added dropwise at 20° C. under argonto a solution of 0.35 g (1.04 mmol) of5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid(WO2006/072736), 0.198 g (1.14 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.165 g(1.14 mmol) of 1-hydroxybenzotriazole monohydrate in 6 ml of drydimethylformamide. The reaction mixture is stirred overnight, run onto100 ml of water and then extracted three times with 50 ml of ethylacetate. The organic phases are subsequently combined, washed threetimes with 20 ml of water, dried over sodium sulfate and thenconcentrated under reduced pressure. The expected product is purified bychromatography on a silica column, elution being carried out with amixture of dichloromethane and methanol. 0.19 g of the expected compoundis thus isolated.

Melting point: 192-193° C.

¹H NMR (d₆-DMSO), δ (ppm): 3.01 (s, 6H); 5.93 (s, 2H) 6.68 (d, 1H); 6.92(m, 2H); 7.06 (t×d, 1H); 7.32 (m, 1H); 7.51 (s, 1H); 7.58 (d, 1H); 7.78(d, 1H); 7.85 (d, 1H); 8.2 (s, 1H); 8.39 (s, 1H); 10.39 (s, 1H).

EXAMPLE 4 Compound No. 16N-[6-(Dimethylamino)-5-methylpyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

Compound No. 16 is prepared from5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO2006/072736)and 3-amino-5-methyl-6-dimethylaminopyridine (GB 870 027) according to aprocess similar to that described in example No. 3.

Melting point: 145-146° C.

¹H NMR (d₆-DMSO), δ (ppm): 2.28 (s, 3H); 2.78 (s, 6H) 5.91 (s, 2H); 6.91(m, 2H); 7.06 (t×d, 1H); 7.26 (t×d, 1H); 7.31 (m, 1H); 7.41 (s, 1H);7.58 (m, 2H); 7.88 (s, 1H); 8.39 (s, 1H); 10.39 (s, 1H).

EXAMPLE 5 Compound No. 19N-[6-(Dimethylamino)-5-methylpyridin-3-yl]-5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxamide5.1 5-Fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxylic acid

A solution of 2.1 g (7.04 mmol) of ethyl5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxylate and 1.18 g(21.12 mmol) of potassium hydroxide in 80 ml of ethanol and 2 ml ofwater is heated at reflux for 2 hours. The reaction mixture issubsequently concentrated under reduced pressure. 100 ml of water areadded and the pH of the solution is brought to pH 8 by addition of aconcentrated hydrochloric acid solution. A precipitate is collected byfiltration and is washed with water and then dried under reducedpressure. 1.5 g of the expected product are thus obtained.

Melting point: 282-283° C.

5.2N-[6-(Dimethylamino)-5-methylpyridin-3-yl]-5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxamide(Compound No. 19)

Compound No. 19 is prepared from5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxylic acid, synthesizedin stage 5.1, and 3-amino-5-methyl-6-(dimethylamino)pyridine (GB 870027) according to a process similar to that described in example No. 3.

Melting point: 164-165° C.

¹H NMR (d₆-DMSO), δ (ppm): 2.28 (s, 3H); 2.75 (s, 6H) 5.91 (s, 2H); 6.99(d, 2H); 7.26 (t×d, 1H); 7.46 (s, 1H); 7.58 (m, 2H); 7.85 (s, 1H); 8.36(s, 1H); 8.49 (d, 2H); 10.39 (s, 1H).

EXAMPLE 6 Compound No. 20N-[6-(Dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

Compound No. 20 is prepared from5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO2006/072736)and 3-amino-5-trifluoromethyl-6-(dimethylamino)pyridine according to aprocess similar to that described in example No. 3.

Melting point: 142-143° C.

¹H NMR (d₆-DMSO), δ (ppm): 2.89 (s, 6H); 5.89 (s, 2H) 6.88 (m, 2H); 7.03(t×d, 1H); 7.15 (t×d, 1H); 7.31 (m, 1H); 7.42 (s, 1H); 7.59 (m, 2H); 8.4(s, 1H); 8.72 (s, 1H); 10.65 (s, 1H)

EXAMPLE 7 Compound No. 11N-[6-(Acetylamino)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

Compound No. 11 is prepared from5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO 2006/072736)and 6-acetylamino-3-aminopyridine according to a process similar to thatdescribed in example No. 3.

Melting point: 252-254° C.

¹H NMR (d₆-DMSO), δ (ppm): 2.08 (s, 3H); 5.89 (s, 2H) 6.89 (m, 2H); 7.01(t×d, 1H); 7.15 (t×d, 1H); 7.29 (m, 1H); 7.41 (s, 1H); 7.58 (m, 2H);8.06 (s, 2H); 8.68 (s, 1H); 10.42 (s, 1H); 10.56 (s, 1H).

EXAMPLE 8 Compound No. 21N-[6-Methylamino-2-methylpyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide8.1 6-Methylamino-2-methyl-3-aminopyridine (Compound No. Va)

A suspension of 0.4 g (2.39 mmol) of6-methylamino-2-methyl-3-nitropyridine (Prace Naukowe AkedimiiEkonomicznej imienia Oskara Langego we Wroclawiu (1988), 435, 119-28)and 0.1 g of 10% palladium-on-charcoal in 50 ml of methanol is stirredat 20° C. for 6 hours under 4 atmospheres of hydrogen. The reactionmixture is subsequently filtered through a celite plug and thenconcentrated under reduced pressure. 0.33 g of the expected product isthus isolated in the form of an oil which will be used as is in thecontinuation of the synthesis.

8.2N-[6-Methylamino-2-methylpyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide(Compound No. 21)

Compound No. 21 is prepared from5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO2006/072736)and 6-methylamino-2-methyl-3-aminopyridine (Va), prepared in stage 8.1,according to a process similar to that described in example no. 3.

Melting point: 229-230° C.

¹H NMR (d₆-DMSO), δ (ppm): 2.18 (s, 3H); 2.75 (s, 3H) 5.86 (s, 2H); 6.26(d, 1H); 6.36 (m, 1H); 6.85 (d, 1H); 6.91 (d, 1H); 7.03 (t×d, 1H); 7.13(t×d, 1H); 7.22 (d, 1H); 7.31 (m, 1H); 7.35 (s, 1H); 7.51 (d×d, 1H); 7.6(m, 1H); 9.9 (s, 1H).

EXAMPLE 9 Compound No. 27N-[6-Dimethylamino-5-fluoropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

Compound No. 27 is prepared from 0.3 g (1.04 mmol) of5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO2006/072736)and 0.3 g (1.57 mmol) of 6-dimethylamino-5-fluoro-3-aminopyridinehydrochloride (WO2004/110986) according to a process similar to thatdescribed in example No. 3.

Melting point: 158-159° C.

¹H NMR (d₆-DMSO), δ (ppm): 3.11 (s, 6H); 5.89 (s, 2H) 6.8 (d×t, 1H);6.97 (m, 2H); 7.12 (m, 2H); 7.35 (m, 3H); 7.91 (m, 3H).

EXAMPLE 10 Compound No. 28N-[6-Dimethylamino-4-(trifluoromethyl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide10.1 Methyl 6-dimethylamino-4-(trifluoromethyl)-pyridine-3-carboxylate

A mixture of 2.5 g (10.43 mmol) of methyl6-chloro-4-(trifluoromethyl)nicotinate and 18.4 ml (146 mmol) of a 40%solution of dimethylamine in water is heated at 100° C. for 1 hour. Aprecipitate is subsequently collected by filtering the cooled mixtureand is washed with 150 ml of water. After drying under reduced pressure,2.3 g of the expected compound are isolated.

¹H NMR (CDCl₃), δ (ppm): 3.27 (s, 6H); 3.94 (s, 3H); 6.81 (s, 1H); 8.9(s, 1H).

10.2 6-Dimethylamino-4-(trifluoromethyl)pyridine-3-carboxylic acid

A mixture of 2.3 g (9.27 mmol) of methyl6-dimethylamino-4-(trifluoromethyl)pyridine-3-carboxylate, obtained instage 10.1, and 0.78 g (13.9 mmol) of potassium hydroxide in 50 ml ofmethanol and 2 ml of water is stirred at 20° C. for 24 hours. Themixture is subsequently concentrated under reduced pressure. 100 ml ofwater are subsequently added and the solution is washed with 100 ml ofdichloromethane and then acidified to pH 4 by addition of concentratedhydrochloric acid. A precipitate is collected by filtration and iswashed with 50 ml of water. After drying under reduced pressure, 1.7 gof the expected compound are isolated.

¹H NMR (d₆-DMSO), δ (ppm): 3.19 (s, 6H); 6.9 (s, 1H); 8.75 (s, 1H);12.87 (broad peak, 1H).

10.36-Dimethylamino-4-trifluoromethyl-3-(tert-butoxycarbonylamino)pyridine

A mixture of 1.7 g (7.26 mmol) of6-dimethylamino-4-(trifluoromethyl)pyridine-3-carboxylic acid, obtainedin stage 10.2, 2.03 ml (9.44 mmol) of diphenyl phosphoryl azide and 2.53ml (18.15 mmol) of triethylamine in 23 ml of tert-butanol is heated at90° C. for 5 hours. The reaction mixture is subsequently concentratedunder reduced pressure and the residue is taken up in 50 ml of water andextracted 3 times with 50 ml of dichloromethane. The organic phases arecombined, washed with 50 ml of water, dried over sodium sulfate and thenconcentrated under reduced pressure. The oil obtained is purified bychromatography on a silica column, elution being carried out with amixture of dichloromethane and methanol. 0.75 g of the expected productis thus isolated.

¹H NMR (CDCl₃), δ (ppm): 1.39 (s, 9H); 3.07 (s, 6H) 5.91 (broad peak,1H); 6.53 (s, 1H); 8.31 (s, 1H).

10.4 6-Dimethylamino-4-trifluoromethyl-3-aminopyridine hydrochloride(amine Vb)

A solution of 0.73 g (2.39 mmol) of6-dimethylamino-4-trifluoromethyl-3-(tert-butoxycarbonylamino)pyridine,prepared in stage 10.3, in 8.5 ml of 4N hydrochloric acid in dioxane isstirred at reflux for 5 hours. 200 ml of ethyl ether are subsequentlyadded to the cooled reaction mixture. 0.6 g of a precipitate iscollected by filtration.

Melting point: 198-201° C.

¹H NMR (d₆-DMSO), δ (ppm): 3.11 (s, 6H); 7.2 (s, 1H) 7.21 (broad peak,2H); 8.09 (s, 1H).

10.5N-[6-dimethylamino-4-(trifluoromethyl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide(Compound No. 28)

Compound No. 28 is prepared from 0.3 g (1.04 mmol) of5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO2006/072736)and 0.328 g (1.36 mmol) of6-dimethylamino-4-trifluoromethyl-3-aminopyridine hydrochloride,described in stage 10.4, according to a process similar to thatdescribed in example No. 3.

Melting point: 209-210° C.

¹H NMR (CDCl₃), δ (ppm): 3.2 (s, 6H); 5.86 (s, 2H); 6.75 (s, 1H); 6.82(m, 1H); 6.98 (m, 2H); 7.12 (m, 2H); 7.3 (m, 2H); 7.41 (m, 1H); 7.66 (s,1H); 8.61 (m, 1H).

The chemical structures and the physical properties of some compounds ofgeneral formula (I) according to the invention are illustrated in thefollowing table 1.

In this table:

-   -   the “M.p.” column gives the melting points of the products in        degrees Celsius (° C.);    -   in the “Salt/Base” column, “-” represents a compound in the form        of the free base, whereas “HCl” represents a compound in the        hydrochloride form and the ratio in brackets is the base:acid        ratio;    -   “nPr” represents a linear propyl chain, “cycloPr” represents a        cyclopropyl group and “Ac” represents an acetyl group.

TABLE 1 (I)

No. X₁, X₂, X₃, X₄ Y Z₁, Z₂, Z₃, Z₄ NR_(a)R_(b) M.p. (° C.) Salt/Base  1H, F, H, H 3-fluorophenyl CH, CH, CH, N NHCH₃ 225-227 —  2 H, F, H, H3-fluorophenyl CH, CH, CH, N N(CH₃)₂ 232-234 HCl (1:1)  3 H, F, H, Hphenyl CH, CH, CH, N NHCH₃ 246-247 —  4 H, F, H, H phenyl CH, CH, CH, NN(CH₃)₂ 196-197 —  5 H, H, F, H 3-fluorophenyl CH, CH, CH, N N(CH₃)₂194-195 —  6 H, F, H, H 3-fluorophenyl CH, CH, N, CH N(CH₃)₂ 190-192 — 7 H, F, H, H 2-fluorophenyl CH, CH, CH, N NHCH₃ 253-254 —  8 H, F, H, H3-fluorophenyl CH, CH, CH, N NHnPr 132-134 HCl (1:1)  9 H, F, H, H3-fluorophenyl CH, CH, CH, N NHcycloPr 120-140 HCl (1:1) 10 H, F, H, H4-fluorophenyl CH, CH, CH, N N(CH₃)₂ 208-209 — 228-229 HCl (1:1) 11 H,F, H, H 3-fluorophenyl CH, CH, CH, N NHAc 252-254 — 12 H, CF₃, H, H3-fluorophenyl CH, CH, CH, N N(CH₃)₂ 192-193 — 13 H, F, H, H3-fluorophenyl C—CH₃, CH, CH, N N(CH₃)₂ 183-185 — 14 H, H, CF₃, H3-fluorophenyl CH, CH, CH, N NHAc 293-295 — 15 H, F, H, H 3-fluorophenylC—CH₃, CH, CH, N NHCH₃ 215-217 — 16 H, F, H, H 3-fluorophenyl CH, C—CH₃,CH, N N(CH₃)₂ 145-146 — 17 H, F, H, H pyridin-4-yl C—CH₃, CH, CH, NN(CH₃)₂ 217-219 — 18 H, F, H, H pyridin-4-yl C—CH₃, CH, CH, N NHCH₃218-220 — 19 H, F, H, H pyridin-4-yl CH, C—CH₃, CH, N N(CH₃)₂ 164-165 —20 H, F, H, H 3-fluorophenyl CH, C—CF₃, CH, N N(CH₃)₂ 142-143 — 21 H, F,H, H 3-fluorophenyl CH, CH, C—CH₃, N NHCH₃ 229-230 — 22 H, F, H, H3-fluorophenyl CH, CH, N, N N(CH₃)₂ 239-241 HCl (1:1) 169-170 — 23 H,CF₃, H, H 3-fluorophenyl CH, CH, N, N N(CH₃)₂ 138-139 — 24 H, H, CF₃, H3-fluorophenyl CH, CH, N, N N(CH₃)₂ 255-267 — 25 H, CF₃, H, Hpyridin-4-yl CH, CH, N, N N(CH₃)₂ 268-272 HCl (1:1) 26 H, F, H, Hpyridin-4-yl CH, CH, CH, N NHCH₃ 220-222 — 27 H, F, H, H 3-fluorophenylCH, C—F, CH, N N(CH₃)₂ 158-159 — 28 H, F, H, H 3-fluorophenyl C—CF₃, CH,CH, N N(CH₃)₂ 209-210 —

The compounds of the invention were subjected to in vitro and in vivopharmacological assays which demonstrated their advantage as substancespossessing therapeutic activities.

The compounds of the invention also exhibit characteristics ofsolubility in water which favor a good in vivo activity.

Test of the Inhibition of the Current Induced by Capsaicin with Regardto Rat DRGs

-   -   Primary culture of rat dorsal root ganglion (DRG) cells:

The neurons of the DRG naturally express the TRPV1 receptor.

Primary cultures of DRGs of newborn rats are prepared from one-day-oldrats. Briefly, after dissection, the ganglions are trypsinized and thecells dissociated mechanically by gentle trituration. The cells areresuspended in an Eagle's basal culture medium comprising 10% of fetalcalf serum, 25 mM KCl, 2 mM glutamine, 100 μg/ml of gentamicin and 50ng/ml of NGF and then deposited on glass cover slips covered withlaminin (0.25×106 cells per cover slip) which are subsequently placed in12-well Corning dishes. The cells are incubated at 37° C. in ahumidified atmosphere comprising 5% of CO₂ and 95% of air. Cytosineβ-D-arabinoside (1 μM) is added 48 h after culturing, in order toprevent the growth of non-neuronal cells. After culturing for 7-10 days,the cover slips are transferred into experimental chambers for the patchclamp studies.

Electrophysiology:

The measurement chambers (volume 800 μl) comprising the cell preparationare placed on the stage of an inverted microscope (Olympus IMT2)equipped with Hoffman optics (Modulation Contrast, New York) and areobserved at a magnification of 400×. The chambers are continuouslyperfused by gravity (2.5 ml/min) using a distributor of solutions whichhas 8 inlets, the single outlet of which, composed of a polyethylenetube (opening 500 μm), is placed at least 3 mm from the cell studied.The “whole cell” configuration of the patch clamp technique was used.Borosilicate glass pipettes (resistance 5-10 Mohms) are brought close tothe cell using a 3D piezoelectric micromanipulator (Burleigh, PC1000).The overall currents (membrane potential set at −60 mV) are recordedwith an Axopatch 1D amplifier (Axon Instruments, Foster City, Calif.)connected to a PC controlled by Pclamp8 software (Axon Instruments). Thecurrent plots are recorded on paper and simultaneously recordeddigitally (sampling frequency 15 to 25 Hz) and acquired on the hard diskof the PC.

The application of a micromolar capsaicin solution produces an incomingcationic current with regard to the DRG cells (voltage set at −70 mV).In order to minimize the desensitization of the receptors, a minimuminterval of one minute between two applications of capsaicin isobserved. After a control period (stabilization of the capsaicin aloneresponse), the test compounds are applied alone at a given concentration(concentration of 10 nM or 0.1 nM) for a period of time of 4 to 5minutes, during which several capsaicin+compound tests are carried out(obtaining the maximum inhibition). The results are expressed as % ofinhibition of the control capsaicin response.

The percentages of inhibition of the capsaicin (1 microM) response arebetween 20% and 100% for the most active compounds of the inventiontested at a concentration of 10 nM to 0.1 nM (see example in table 2).

The compounds of the invention are thus effective in vitro antagonistsof receptors of TRPV1 type.

TABLE 2 % Inhibition by the DRG Compound No. patch technique 1 53% (1nM) 12 100% (1 nM) 17 60% (10 nM) 19 33% (10 nM)Mouse Corneal Irritation Test

The irritating nature of capsaicin is easily assessed on the corneasince this organ is one of the most innervated by C fibers. In thiscontext, according to preliminary experiments, the application of a verysmall amount of capsaicin (2 μl at a concentration of 160 μM) at thesurface of the cornea of an animal results in a number of kinds ofstereotyped behavior related to irritation which are easy to record.These include: blinking of the eye, rubbing of the instilled eye by theipsilateral front paw, rubbing of the face with the two front paws andscratching of the ipsilateral face by the hind paw. The duration ofthese kinds of behavior does not exceed 2 minutes of observation and theanimal then resumes its normal activity. Its appearance is furthermorealso normal. The mouse does not hide in a corner with the hairs standingon end and does not develop any observable signs of suffering. It may beconcluded therefrom that the duration of action of capsaicin at thesedoses is less than 2 minutes.

Summary of the Methodology:

The principle of the series of experiments is to determine whether thecompounds of the invention can influence the behavioral response inducedby a given amount of capsaicin. Capsaicin is initially diluted to 25 mMin DMSO and is diluted, for its final use, in physiological saline with10% Tween 80. It appears, from control studies, that the solvent has noeffect under these conditions.

In practice, the test product, prepared at 25 mM in DMSO and diluted forits final use in physiological saline with 10% Tween 80 to the strongerconcentration of 500 μM, is administered in local application at thesurface of the cornea under a volume of 2 μl, 10 minutes before theapplication of the capsaicin. The animal receives the ocularinstillation of 2 μl of a 160 μM capsaicin solution prepared asindicated above. During observation for 2 minutes following theinstillation, the number of rubbing actions on the instilled eye by theipsilateral front paw is counted for each animal.

For a given group, the percentage of protection is calculated asfollows:

P=100−((mean number of scratching actions of the group treated with thecompound/mean number of scratching actions of the group treated with thesolvent)×100).

This percentage of protection is converted to a mean for each group ofanimals (n=number of animals tested with the compound of the invention).

The percentages of protection evaluated in this model for the mostactive compounds of the invention, used at a concentration of 500 μM,are between 20% and 100% (see example in table 3):

TABLE 3 Compound No. % P (500 μM) 1 23%

The results of these trials show that the most active compounds of theinvention block the effects induced by the stimulation of the TRPV1receptors.

The compounds of the invention can thus be used for the preparation ofmedicaments, in particular for the preparation of a medicament intendedto prevent or to treat pathologies in which receptors of TRPV1 type areinvolved.

Thus, according to another of its aspects, a subject matter of theinvention is medicaments which comprise a compound of formula (I) or apharmaceutically acceptable salt or also a hydrate or a solvate of saidcompound.

These medicaments are employed in therapeutics, in particular in theprevention and/or the treatment of pain and inflammation, chronic,neuropathic (traumatic, diabetic, metabolic, infectious, toxic, inducedby an anticancer treatment or iatrogenic), (osteo)arthritic or rheumaticpain, fibromyalgia, bone pain, cancer-related pain, trigeminalneuralgia, cephalgia, migraine, dental pain, burns, sunburn, bites orstings, post-herpetic neuralgia, muscle pain, nerve compression (centraland/or peripheral), marrow and/or brain trauma, ischemia (of the marrowand/or brain), neurodegeneration, hemorrhagic vascular accidents (of themarrow and/or brain) or post-stroke pain.

The compounds of the invention can be used for the preparation of amedicament intended to prevent and/or to treat urological disorders,such as bladder hyperactivity, bladder hyperreflexia, bladderinstability, incontinence, urgent urination, urinary incontinence,cystitis, renal colic, pelvic hypersensitivity and pelvic pain.

The compounds of the invention can be used for the preparation of amedicament intended to prevent and/or to treat gynecological disorders,such as vulvodynia, salpingitis-related pain or dysmenorrhea.

These products can also be used for the preparation of a medicamentintended to prevent and/or to treat gastrointestinal disorders, such asgastro-esophageal reflux disorder, stomach ulcers, duodenal ulcers,functional dyspepsia, colitis, IBS, Crohn's disease, pancreatitis,esophagitis or biliary colic.

The compounds of the invention can also be used for the preparation of amedicament intended to treat diabetes.

Likewise, the products of the present invention may be of use in theprevention and/or the treatment of respiratory disorders, such asasthma, coughs, COPD, bronchoconstriction and inflammatory disorders.These products can also be used to prevent and/or to treat psoriasis,pruritus, irritation of the skin, eyes or mucous membranes, herpes orshingles.

The compounds of the invention can also be used for the preparation of amedicament intended to treat depression.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions comprisean effective dose of at least one compound according to the invention,or a pharmaceutically acceptable salt, a hydrate or a solvate of saidcompound, and at least one pharmaceutically acceptable excipient.

Said excipients are chosen, according to the pharmaceutical form and themethod of administration desired, from the usual excipients known to aperson skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or its optional salt, solvate orhydrate, can be administered in unit administration form, as a mixturewith conventional pharmaceutical excipients, to animals and human beingsfor the prophylaxis or the treatment of the disorders or diseasesmentioned above.

The appropriate unit administration forms comprise oral forms, such astablets, soft or hard gelatin capsules, powders, granules and oralsolutions or suspensions, sublingual, buccal, intratracheal, intraocularand intranasal administration forms, forms for administration byinhalation, topical, transdermal, subcutaneous, intramuscular orintravenous administration forms, rectal administration forms andimplants. The compounds according to the invention can be used, fortopical application, in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in the tablet form can comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mgCroscarmellose sodium 6.0 mg Corn starch 15.0 mgHydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

Said unit forms comprise doses in order to make possible dailyadministration of 0.001 to 30 mg of active principle per kg of bodyweight, depending on the pharmaceutical dosage form.

There may be specific cases where higher or lower dosages areappropriate; such dosages do not depart from the scope of the invention.According to the usual practice, the dosage appropriate to each patientis determined by the physician according to the method of administrationand the weight and response of said patient.

The present invention, according to another of its aspects, also relatesto a method for the treatment of the pathologies indicated above whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or one of its pharmaceuticallyacceptable salts or hydrates or solvates.

1. A compound of the formula (I):

wherein: X₁ is selected from the group consisting of hydrogen, halogen,C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, cyano, C(O)NR₁R₂, nitro, C₁-C₆-thioalkyl,—S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, aryl-C₁-C₆-alkylene,aryl and heteroaryl; wherein the aryl and heteroaryl are optionallybeing substituted by one or more substituents chosen from halogen,C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, nitro or cyanogroup; X₂ is selected from the group consisting of hydrogen, halogen,C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁C₆-fluoroalkoxy, cyano, C(O)NR₁R₂, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, aryl-C₁-C₆-alkylene, aryl and heteroaryl;wherein the aryl and heteroaryl optionally being substituted by one ormore substituents chosen from halogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, nitro or cyano group; X₃ and X₄ represent,independently of one another, hydrogen, halogen, C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxy,cyano, C(O)NR₁R₂, nitro, NR₁R₂, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅, aryl-C₁-C₆-alkylene,aryl or heteroaryl, the aryl and heteroaryl optionally being substitutedby one or more substituents chosen from halogen, C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, nitro or cyano group; Z₁, Z₂, Z₃ andZ₄ represent, independently of one another, nitrogen or a C(R₆) group,wherein at least one of said group is nitrogen and at least one of saidgroup is a C(R₆) group; and wherein the nitrogen atom or one of thenitrogen atoms present in the ring, defined as nitrogen of position 1,optionally being substituted by R₇ when the carbon atom in the 2 or 4position with respect to this reference nitrogen is substituted by anoxo or a thio group; n is equal to 0, 1, 2 or 3; Y is selected from thegroup consisting of aryl and heteroaryl both of which are optionallysubstituted by one or more groups chosen from halogen, C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,hydroxy, C₁-C₆-alkoxy, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₁R_(2,)nitro, NR₁R₂, C₁-C₆-thioalkyl,thiol, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄,NR₃SO₂R₅, aryl-C₁-C₆-alkylene or aryl group, the aryl and thearyl-C₁-C₆-alkylene optionally being substituted by one or moresubstituents chosen from halogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, nitro or cyano group; Ra and Rb represent,independently of one another, hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, hydroxy,C₁-C₆-alkoxy, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxy,aryl or heteroaryl group, it being possible for Ra and Rb optionally tobe substituted by one or more Rc groups which are identical to ordifferent from one another; Rc is selected from the group consisting ofhalogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxy, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, cyano, C(O)NR₁R₂, NR₁R₂, S(O)NR₁R₂, NR₃COR₄,NR₃SO₂R₅, OC(O)NR₁R₂, NR₃COOR₄, NR₃CONR₁R₂, hydroxy, thiol, oxo, thio,aryl-C₁-C₆-alkylene, aryl and heteroaryl; wherein the aryl and theheteroaryl optionally being substituted by one or more substituentschosen from halogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxy, nitro or cyano group; R₁ and R₂ represent,independently of one another, hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene or aryl group; orR₁ and R₂ together form, with the nitrogen atom which carries them, anazetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl,thiomorpholinyl, piperazinyl or homopiperazinyl group, said groupoptionally being substituted by a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene, aryl or heteroarylgroup; R₃ and R₄ represent, independently of one another, hydrogen,C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,aryl-C₁-C₆-alkylene, aryl or heteroaryl group; R₅ representsC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,aryl-C₁-C₆-alkylene, aryl or heteroaryl group; R₆ represents hydrogen,halogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxy, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkylene, heteroaryl, hydroxy,thiol, oxo or thio group; and R₇ represents hydrogen, C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl,aryl, aryl-C₁-C₆-alkylene or heteroaryl group; it being possible for thenitrogen atom or atoms of the compound of general formula (I) to be inthe oxidized form; or a salt thereof.
 2. The compound of formula (I) asclaimed in claim 1, wherein X₁, X₂, X₃ and X₄ are chosen, independentlyof one another, from hydrogen, halogen, C₁-C₆-alkyl or C₁-C₆-fluoroalkylgroup.
 3. The compound of formula (I) as claimed in claim 2, wherein X₁and X₄ represent hydrogen, and X₂ and X₃ are chosen, independently ofone another, from hydrogen, halogen or C₁-C₆-fluoroalkyl group.
 4. Thecompound of formula (I) as claimed in claim 1, wherein Z₁, Z₂, Z₃ and Z₄represent, independently of one another, nitrogen or C(R₆) group, andwherein at least two of them are C(R₆) group; the nitrogen atom or oneof the nitrogen atoms present in the ring, defined as nitrogen ofposition 1, optionally being substituted by R₇ when the carbon atom inthe 2 or 4 position with respect to this reference nitrogen issubstituted by an oxo or thio group; R₆ and R₇ being as defined inclaim
 1. 5. The compound of formula (I) as claimed in claim 4, whereinZ₁ and Z₂ represent C(R₆) and Z₃ and Z₄ represent nitrogen, and whereinR₆ is hydrogen.
 6. The compound of formula (I) as claimed in claim 4,wherein Z₁, Z₂, Z₃ and Z₄ represent, independently of one another,nitrogen or C(R₆) group, and wherein one of said group is nitrogen andthe others are C(R₆) group; the nitrogen atom present in the ring,defined as nitrogen of position 1, optionally being substituted by R₇when the carbon atom in the 2 or 4 position with respect to thisreference nitrogen is substituted by an oxo or thio group; R₆ and R₇being as defined in claim
 1. 7. The compound of formula (I) as claimedin claim 6, wherein Z₁ and Z₂ represent a C(R₆) group and Z₃ and Z₄represent, independently of one another, nitrogen or a C(R₆) group, oneof Z₃ and Z₄ is a C(R₆) group, and wherein R₆ is hydrogen, halogen,C₁-C₆-alkyl or C₁-C₆-fluoroalkyl.
 8. The compound of formula (I) asclaimed in claim 7, wherein Z₄ is nitrogen and Z₁, Z₂ and Z₃ represent,independently of one another, C(R₆) group, and wherein R₆ is hydrogen,halogen, C₁-C₆-alkyl or C₁-C₆-fluoroalkyl.
 9. The compound of formula(I) as claimed in claim 8, wherein n is
 1. 10. The compound of formula(I) as claimed in claim 9, wherein Y is aryl or heteroaryl optionallysubstituted by one or more halogen atoms.
 11. The compound of formula(I) as claimed in claim 10, wherein Ra and Rb represent, independentlyof one another, hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, hydroxy,C₁-C₆-alkoxy or C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, it being possiblefor Ra and Rb to be optionally substituted by one or more Rc groupswhich are identical to or different from one another; and wherein Rc isC₁-C₆-alkoxy, NH₂ or hydroxy.
 12. The compound of formula (I) as claimedin claim 10, wherein Ra and Rb represent, independently of one another,hydrogen, C₁-C₆-alkyl or C₃-C₇-cycloalkyl, it being possible for Ra andRb to be optionally substituted by one or more Rc groups which areidentical to or different from one another; and wherein Rc is an oxogroup.
 13. A process for the preparation of a compound of formula (I) asclaimed in claim 1, comprising: reacting a compound of formula (IV):

wherein X₁, X₂, X₃, X₄, Y and n are as defined in claim 1 and B ischlorine, with an amine of formula (V):

wherein Z₁, Z₂, Z₃, Z₄, Ra and Rb are as defined in claim 1, in asolvent.
 14. A process for the preparation of a compound of formula (I)as claimed in claim 1, comprising: reacting a compound of formula (IV):

wherein X₁, X₂, X₃, X₄, Y and n are as defined in claim 1 and B ishydroxy, with an amine of formula (V):

wherein Z₁, Z₂, Z₃, Z₄, Ra and Rb are as defined in claim 1, in thepresence of a coupling agent and a base in a solvent.
 15. Apharmaceutical composition comprising a compound of formula (I) asclaimed in claim 1 or a pharmaceutically acceptable salt thereof, incombination with at least one pharmaceutically acceptable excipient. 16.A pharmaceutical composition comprising a compound of formula (I) asclaimed in claim 12 or a pharmaceutically acceptable salt thereof, incombination with at least one pharmaceutically acceptable excipient. 17.A method of treating a disease in which receptors of TRPV1 are involvedin a patient comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I) as claimed in claim 1wherein said disease is selected from the group consisting of pain,inflammation, urological disorders, gynecological disorders,gastrointestinal disorders, respiratory disorders, psoriasis, pruritus,irritation of the skin, eyes or mucous membranes, herpes or shingles,depression and diabetes.